Chronic inflammation is characterized by prolonged inflammation that lasts weeks or months. It involves ongoing tissue injury, inflammation, and attempts at repair. It can follow acute inflammation or begin slowly and persistently. Common causes include persistent infections, autoimmune diseases, allergies, exposure to toxins, and certain cancers. Morphologically, it features mononuclear cell infiltration including lymphocytes, macrophages and plasma cells, as well as tissue destruction and attempts at healing. Macrophages and lymphocytes interact bidirectionally to amplify and sustain the inflammatory response. Granulomatous inflammation forms collections of activated macrophages and lymphocytes that aim to contain pathogens that are difficult to eliminate.

1. CHRONIC INFLAMMATION
Dr. P. Shanthi DCP

2. Chronic inflammation
• Inflammation of prolonged duration (weeks or
months)
• Tissue injury, inflammation and attempts at
repair coexist in varying combinations

3. Chronic inflammation
• Follow acute inflammation
• Begin insidiously, as a low grade smoldering
response
• Eg - RA, Atherosclerosis, TB, Pulmonary
fibrosis,
• Degenerative disorders (Alzheimers, cancer)

4. Causes
• Persistent infection – virus, fungi, TB (Granulomatous-Type IV
• Immune mediated inflammatory disease – autoimmune
diseases
(self Ag’s - RA, multiple sclerosis microbes - IBD)
• Allergic disorders – Environmental antigens - BA (acute and
chronic)
• Prolonged exposure to toxins
Exogenous – silicosis – Nondegradable inanimate
material
Endogenous – lipid (Atherosclerosis)
• Neurodegenerative diseases – Alzheimer
• Metobolic syndromes – DM-2
• Certain cancers

5. Chronic inflammation –
Morphologic features
• Mononuclear cell
infiltration –
lymphocytes,
macrophages and plasma
cells
• Tissue destruction
• Attempts at healing
(angiogenesis and fibrosis)

6. Macrophages in Chronic inflammation
Activated macrophage - Mononuclear Phagocyte
System (MPS). monocyte macrophage
• Bone marrow derived
Resident macrophages –
• yolk sac & fetal liver derived

8. Resident macrophages
• Liver – Kupffer cells
• Spleen and lymph node – Sinus histiocyte
• Lung – Alveolar macrophage
• CNS – Microglia
Arise from
• Bone marrow
• Yolk sac or fetal liver, very early in embryogenesis
Extravasation – governed by cytokines, adhesion
molecules and cellular interactions

9. Macrophage activation
• Classical pathway
• Alternate pathway

11. Cells of chronic inflammation
• Macrophage
• Lymphocyte - T cells & Activated B cells
• Plasma cells
• Other cells – Eosinophils, Neutrophils

12. Funtions of macrophage
• Ingest and eliminate microbes and dead
tissues
• Initiate the process of tissue repair (scar)
• Secrete mediators of inflammation
• Display antigens to T cells and respond to
signals from T cells
• Powerful defence mechanism – tissue
destruction

13. Role of lymphocytes
• CD4+ T lymphocyte promote inflammation
• Act along with macrophages in a bidirectional
way
• Amplify the early reaction

14. Macrophage-lymphocyte interactions in
chronic inflammation

15. CD4+ T Lymphocytes
Type Mediator secreted Function Defence against
TH1 IFN-γ Activates
macrophage by
Classical pathway
(M1)
Virus, bacteria,
autoimmune
diseases
TH2 IL-4, IL-5, and IL-13 Recruit eosinophil
Activate
macrophage by
alternate pathway
(M2)
Helminths
Allergic reactions
TH17 IL- 17 Recruit neutrophil
Role In IBD
Virus, bacteria,
autoimmune
diseases

16. Tertiary lymphoid organs – a type of
lymphoid organogenesis
• Thyroid –
Hashimoto’s thyroiditis
• Synovium –
Rheumatoid arthritis

17. Eosinophils
• IgE mediated
• Recruitment - Eotaxin
by WBC & epithelial
cells
• Major basic protein -
toxic to parasites and
epithelial cells

18. • Participate in both
acute & chronic
inflammatory reactions
• Have a receptor that
binds Fc portion of IgE
antibody
Acute inflammation →
anaphylaxis
Chronic inflammation
→ fibrosis
Mast cells

19. Neutrophils in chronic inflammation
• Persistent microbial infection - Chronic
osteomyelitis
• Persistent mediators by activated
macrophages – e.g IBD

20. • Non-specific – chronic osteomyelitis, lung
abscess
• Granulomatous – TB, leprosy, syphilis,
actinoycosis, sarcoidosis
Morphologic types of chronic
inflammation

21. Granulomatous inflammation

22. • Sylvius 17th Cent
– Gross description of tubercle
• Laennec 18th Cent
– Unification of lesions ranging from granular to
conglomerate masses
• Virchow: Microscopic descriptions
– Post inflammatory infiltration
– Nodular ‘tubercle’
Granulomatous inflammation
‘Granul’ (Granulation) ‘oma’ (tumor-like)

23. Granulomatous inflammation
• Form of chronic inflammation characterized by
collections of activated macrophages, often with T
lymphocytes, and sometimes associated with central
necrosis
• Attempt to contain an offending agent which is
difficult to eradicate
• Tissue injury
Morphology - Microscopic collections of histiocytes
(modified as epithelioid cells) with peripheral
rimming of lymphocytes.

24. Granuloma formation
• Chronic macrophage activation (cytokine
mediated)

26. Epithelioid cells
• Epithelioid cells – macrophage with abundant
cytoplasm ( resemble epithelial)
• Fuse and form – multinucleate giant cells
• Two types – granuloma
1. Foreign body granuloma
2. Immune granuloma

27. Foreign body granuloma
• Inert foreign body - talc,sutures,fibres
• FB in the centre of granuloma - viewed with
polarized light appears refractile.
• No specific inflammatory or immune response
• Epithelioid cells and giant cells are apposed to
the surface of the foreign body.

28. Immune granuloma
• Agents causing Persistent T cell activation
• Inciting antigen – difficult to eradicate
• Persistent microbe
• Self antigen
• Macrophage, T cell – IL-2, IFN-γ mediated

29. TB Granuloma
Epithelioid cells
Giant cells
Caseation necrosis

30. Causes of granuloma formation
Condition Mechanism / underlying cause Morphology
Tuberculosis Chronic macrophage activation due to
persistent mycobacterium tuberculosis
Caseating granuloma
Leprosy mycobacterium Leprae Non caseating granuloma
Fungal Infection Aspergillus, zygomycosis Non caseating granuloma
enclosing hyphae
Syphillis Treponema palidum Gumma (plasma cells )
Liver – hepar lobatum
Sarcoidosis Unknown etiology Non caseating granuloma
with abundant activated
macrophage
Crohns disease Immune reaction against self antigens or
intestinal microbes
Non caseating granulomas
Cat scratch
disease
Gram negative bacillus Stellate abscess/ granuloma
Central neutrophils, granular
debris

33. – Microgranulomas
• Collection of 5-10 macrophages (brucellosis,
toxoplasmosis)
– Diffuse
• Sheets of histiocytes, often foamy with poor
lymphocyte component (Leprosy (LL), granulomas in
immunodeficient individuals)
Classification
(Morphological)

34. – Tuberculoid - ‘Classical’ architecture
» Caseating - TB, neural leprosy,
cocciodomycosis
» Non-caseating - Sarcoid, leprosy, syphilis,
fungal, exogenous/endogenous substances
– Suppurative
• LGV, catscratch disease, actinomycosis, yersinia,
tularaemia
Classification
(Morphological)

37. Classification (Aetiological)
A. INFECTIVE
• Bacterial - TB, Syphilis, Leprosy, Brucellosis, Yersinia, Cat
scratch disease
• Rickettsia - Typhus
• Chlamydia - LGV,
• Fungal - Histoplasma, Cryptococcus, Blastomyces,
Aspergillus
• Protozoal - Toxoplasmosis
• Helminthic - Filariasis, Trichinellosis, Schistosomiasis

38. Classification
(Aetiological)
B. CHEMICAL
• Exogenous - Berylliosis, Silicosis, Asbestosis, Talc
• Endogenous - Urate (Gout), Lipid (Xanthogranuloma), keratin
(Epidermal cysts)
C.ALLERGIC/HYPERSENSISTIVITY - PAN, SLE, RA, Rheumatic fever,
PBC, Lupoid hepatitis

39. Classification
(Aetiological)
D. UNKNOWN • Sarcoidosis
• Crohn’s disease
• Chronic granulomatous disease of
the new born
• ‘Eosinophilic granuloma’
(Histiocytosis X)

40. Classification
(Immunological)
• Low turn over
– Inert insoluble material
(exogenous subs)
– Poor innate immune
response:CMI (Leprosy
LL, AIDS)
• High turn over
– Strong antigenic
stimulus
– High CMI (TB in
immunocompetent, TT
Leprosy)

41. • Variable size and shape 8-40ū, abundant cytoplasm,
prominent nucleus, solitary nucleolus, ingested particles.
• EM: Complexity and enfolding of nuclei, round to indented,
primary & secondary lysosomes / phagolysosomes, free
ribosomes (RER in epithelioid cells), large Golgi
• Cytochem: Non-specific esterase, acid phosphatase,
peroxidase, muramidase, ATPase
• IHC: Lysozyme, α1 AT, α1 Anti Chymotrypsin, HLA-DR, S-100,
CD 68
• Imm: sIg, C3
Macrophages: Structure

42. • Monocyte (blood)
• Histiocyte/macrophage (tissues)
• Kupffer cell (Liver),
• Alveolar macrophages (lung)
• Sinus histiocyte (lymph node, spleen)
• Tingible body macrophage ‘Fleming’ bodies (follicles of lymph
nodes)
• Dendritic reticulum cell (lymph node interfollicular)
• Osteoclast (bone)
• Microglial cell (CNS)
• Langerhans cell (skin)
• Type A cell (synovium)
• Epithelioid cell
• Giant cells (Inflammation)
Macrophages:Nomenclature

43. • Macrophages
– Histiocytes
– Epithelioid cells: Good immunity, bacterial load low,
effective elimination, infectious agent difficult to
demonstrate
– Foam cells; Lower immunity, effective uptake but poor
elimination, agent easy to demonstrate
– Giant cells
• Lymphocytes
• Plasma cells
• Fibroblasts
Cellular components of granulomas

44. ‘Classical’ Tuberculoid granuloma
…………..
…………..
Langhans
giant cell
Epithelioid
cells
Lymphocytes
Fibroblasts
Caseation

45. Types of giant cells

46. • Physiological
• Syncitiotrophoblast
• Osteoclast
• Sarcolemmal giant cells
• Regenerative
• Skeletal muscle
• Fusion of epithelial/endothelial cells (Viral
induced)
• Herpes giant cells
• Warthin Finkeldey giant cells- Measles (Lymph nodes,
tonsil, lung)
Types of giant cells

47. • Fusion of macrophages
• Langhans, FB, Touton, Cholesterol, Aschoff/Anitschow
cells
• Tumor giant cells
• Benign
• Chondroblastoma, Chondromyxoid fibroma, GCT,
GCT of tendon sheath, Benign fibrous histiocytoma
• Malignant
• Epithelial: Lung , thyroid, choriocarcinoma
• Mesenchymal: Osteosarc., chondrosarc, MFH,
Angiosarc
• Lymphomas: Hodgkins, ALCL
Types of giant cells

48. • Mixed pyogenic and granulomatous
– Blastomyces, Chromoblastomycosis, Mycetoma
• Histiocytic granuloma
– Histoplasma, Meningeal cryptococcosis
• Granuloma with caseation
– Histoplasma, Coccidioides
• Sarcoid type granuloma
– Cryptococcus, Occ Histoplasma
• Fibrocaseous pulmonary granuloma
– Histoplasmosis, Coccidioides, Cryptococcus
Patterns of fungal granulomas

49. Ancillary studies
• Granuloma – first rule out tuberculosis
• Special stains
• Acid fast stain – Mycobacterium
• Culture methods – Fungus, TB
• PCR methods – molecular techniques -TB
• Serological studies (VDRL) – Syphilis
• ACE, Vitamin D level – Sarcoidosis

50. Acute Phase Protein Side effect Mechanisms
SAA Amyloidosis Prolonged production in
Chronic inflammation
Hepcidin Anaemia of chronic
disease
Reduces iron availablity

52. THANK YOU